Commentary

Effect of HAART on natural history of AIDS-related opportunistic disorders

We hypothesized that infection rates following total joint arthroplasty (TJA) in those with the human immunodeficiency virus (HIV) without hemophilia or drug use would be similar to rates in HIV-negative patients. Records at an urban HIV referral hospital were searched for patients who underwent primary total hip and knee arthroplasty from 2003 to 2010. The primary outcome was revision for infection. 372 HIV-negative and 22 HIV-positive TJA patients met inclusion criteria. The HIV-positive group had more deep infections than the HIV-negative group (9.1% v 2.2%, P = 0.102). There were no infections in those with AIDS-defining CD4 counts. Those with HIV may have a higher risk of developing a deep infection. A low CD4 count is not an absolute contraindication to TJA in HIV positive patients.

This retrospective cohort study evaluated the risk of hepatotoxicity in HIV-1 positive pregnant and non-pregnant women starting combined ART.

Data were used from the ATHENA observational cohort. The study population consisted of HIV-1 infected, therapy naïve, pregnant and non-pregnant women, followed between January 1997 and February 2008. Demographic, treatment and pregnancy related data were collected. Risk of hepatotoxicity was determined using univariate and multivariate logistic regression. Analyses were adjusted for age, region of origin, baseline HIV-RNA levels and CD4 cell counts, cART regimen and hepatitis B and C coinfection. ALT and AST values of more than 5 times ULN were considered as hepatotoxicity.

Four-hundred and twenty-five pregnant and 1121 non-pregnant women were included. Independent risk factors of hepatotoxicity in all women were the presence of detectable HCV RNA (OR 5.48, 95% CI 2.25–13.38, p < 0.001) and NVP use (OR 2.63, 95% CI 1.54–4.55, p < 0.001). Stratified for pregnancy, the adjusted risk of hepatotoxicity was significantly associated with HCV coinfection only during pregnancy (OR 23.53, 95% CI 4.69–118.01, p < 0.001). NVP use is related to hepatotoxicity in pregnant (OR 5.26, 95% CI 1.61–16.67, p < 0.005) as well as in non-pregnant women (OR 2.13, 95% CI 1.11–4.00, p = 0.02).

HCV coinfection and NVP use are associated with a higher risk of cART induced hepatotoxicity in pregnant women.

Efectuar una actualización de las recomendaciones sobre el tratamiento antiretroviral (TARV) de los adultos infectados por el VIH-1.

Estas recomendaciones se han consensuado por un panel del Grupo de Estudio de Sida y del Plan Nacional sobre el Sida. Se han revisado los avances en la fisiopatología del VIH-1, los resultados de eficacia y seguridad de ensayos clínicos, estudios de cohortes y de farmacocinética, publicados en revistas biomédicas o presentados en congresos en los últimos años. Se han definido tres niveles de evidencia según la procedencia de los datos: estudios aleatorizados (nivel A), de cohortes o de caso-control (nivel B), u opinión de expertos (nivel C). En cada una de las situaciones se ha establecido recomendar, considerar o no recomendar el TARV.

Actualmente, el TARV con combinaciones de tres fármacos constituye el tratamiento de inicio de elección de la infección crónica por el VIH-1. Estas pautas deben incluir 2 análogos de nucleósido o nucleótido (AN)+1 no análogo (NN) o 2 AN+ 1 inhibidor de la proteasa (IP) potenciado con ritonavir. En los pacientes con infección por VIH-1 sintomática se recomienda iniciar el TARV. En los pacientes asintomáticos el inicio de TARV se basará en la cifra de linfocitos CD4+/μl y en la carga viral plasmática (CVP): 1) en pacientes con linfocitos CD4+ < 200 células/μl se recomienda iniciar el TARV; 2) en pacientes con linfocitos CD4+ entre 200 y 350 células/μl en la mayoría de las ocasiones se debe recomendar el tratamiento, si bien se podría diferir cuando la cifra de linfocitos CD4+ se mantiene próxima a 350 células/μl y la CVP es baja; 3) en los pacientes con linfocitos CD4+ > 350 células/μl se puede diferir el inicio del TARV. El objetivo del TARV es lograr una carga viral plasmática indetectable. Las opciones terapéuticas en los fracasos del TARV se ven limitadas por la aparición de resistencias cruzadas. Los estudios genotípicos en estos casos son de utilidad. Se puede encontrar más información sobre los estudios analizados, las recomendaciones del panel sobre adherencia, toxicidad, tratamiento de la embarazada, pacientes coinfectados por VHB o VHC o sobre la profilaxis postexposición en la página web www.gesida.seimc.org.

La cifra de linfocitos CD4+ es el factor de referencia más importante para iniciar el TARV en pacientes asintomáticos. Por otra parte, el número considerable de fármacos disponibles, los métodos más sensibles de monitorización de la CVP y la posibilidad de determinar las resistencias hacen que las estrategias terapéuticas deban ser cada vez más, mucho más individualizadas.

This consensus document is an update of antiretroviral therapy (ART) recommendations for adult patients infected with the human immunodeficiency virus (HIV-1).

To formulate these recommendations, a panel composed of members of the Grupo de Estudio de Sida (GESIDA; AIDS Study Group) and the Plan Nacional sobre el Sida (PNS; Spanish AIDS Plan) reviewed the advances in the current understanding of the pathophysiology of HIV, the safety and efficacy findings from clinical trials, and the results from cohort and pharmacokinetic studies published in biomedical journals or presented at scientific meetings over the last years. Three levels of evidence were defined according to the source of the data: randomized studies (level A), cohort or case-control studies (level B), and expert opinion (level C). The decision to recommend, consider or not recommend ART was established in each situation.

Currently, the treatment of choice for chronic HIV infection is the combination of three drugs of two different classes, including 2 nucleosides or nucleotide analogs (NRTI) plus 1 non-nucleoside (NNRTI) or 1 boosted protease inhibitor (PI/r). Initiation of ART is recommended in patients with symptomatic HIV infection. In asymptomatic patients, initiation of ART is recommended on the basis of CD4+ lymphocyte counts and plasma viral load, as follows: 1) therapy should be started in patients with CD4+ counts of < ;200 cells/μl; 2) therapy should be started in most patients with CD4+ counts of 200-350 cells/μl, although it can be delayed when CD4+ count persists at around 350 cells/μL and viral load is low, and 3) initiation of therapy can be delayed in patients with CD4+ counts of > 350 cells/μL. The initial objective of ART is to achieve an undetectable viral load. Adherence to therapy plays an essential role in maintaining the antiviral response. Therapeutic options are limited with the development of cross resistance and ART failure. Genotype studies are useful in these cases. More information regarding the studies analyzed and the panel recommendations for adherence, toxicity, treatment during pregnancy, patients with hepatitis B or C virus co-infection, and post-exposure prophylaxis can be accessed at www.gesida.seimc.org

CD4+ lymphocyte count is the most important reference factor for initiating ART in asymptomatic patients. The large number of available drugs, the increased sensitivity of tests to monitor viral load, and the ability to determine viral resistance is leading to a more individualized approach to therapy.

Fonsecaea pedrosoi is the principal causative agent of chromoblastomycosis, which is a chronic, often debilitating, suppurative and granulomatous mycosis. Very little is known about the hydrolytic enzymes produced by this human fungal pathogen. In the present study, we have identified extracellular proteolytic activity from F. pedrosoi mycelial forms when grown in chemically defined conditions. Secretory aspartyl peptidase activity was measured during 15 days of fungal growth in vitro using bovine serum albumin (BSA) as the soluble substrate and extreme acidic pH (2.0). This activity was totally inhibited by pepstatin A, a classic aspartyl peptidase inhibitor. Conversely, metallo (o-phenanthroline), cysteine (E-64) and serine (PMSF) proteolytic inhibitors failed to restrain proteolytic activity. We also evaluated the effect of four distinct HIV aspartyl peptidase inhibitors on the secretory proteolytic activity of F. pedrosoi mycelia. Indinavir, ritonavir and nelfinavir powerfully inhibited extracellular aspartyl proteolytic activity by approximately 97, 96 and 87%, respectively, whereas saquinavir did not significantly interfere with BSA hydrolysis. Mycelial-derived secretory aspartyl peptidase activity cleaved other proteinaceous substrates, including human albumin, fibrinogen, fibronectin, laminin and type I collagen. As previously reported by our group, conidia also produce secretory aspartyl peptidase. In this sense, we investigated the effect of pepstatin A on F. pedrosoi development. Pepstatin A was able to inhibit the growth of conidium and its transformation into mycelium. Taken together, our results suggest a possible participation of aspartyl peptidases in the essential fungal processes, such as growth, differentiation, nutrition and cleavage of relevant host proteinaceous components.